PROJECT SUMMARY/ABSTRACT This is a K23 award application for Dr. Adam de Havenon, a neurologist and young investigator pursuing patient-oriented clinical research on ischemic stroke caused by intracranial atherosclerosis. A K23 award will provide him with the means to acquire critical skills in three key career development areas: 1) biostatistics and clinical trial design, 2), the biology of atherosclerosis and 3) translational MRI research. By acquiring these skills, Dr. de Havenon will fulfill his career goal of becoming an independent investigator who can bridge the disciplines of neuroimaging research and clinical trials in vascular neurology. To pursue this goal, Dr. de Havenon has assembled the mentoring team of Drs. Dennis Parker (primary mentor), an MRI physicist with expertise in neuroimaging evaluation of the cerebrovasculature, and Jennifer Majersik (co-mentor), a neurologist with expertise in stroke epidemiology and clinical trial design. Complementing them is a four person Advisory Committee with authorities in biostatistics, clinical trials, intracranial atherosclerosis, and MRI. Intracranial atherosclerosis is the most common cause of stroke in the world and has the highest rate of stroke recurrence. Based on recent evidence and his own preliminary data, Dr. de Havenon?s central hypothesis is that ischemic stroke in intracranial atherosclerosis is due to macrophage-mediated vulnerability. We will test this hypothesis with the powerful new vessel wall MRI technique combined with an MRI contrast that labels macrophages in intracranial atherosclerosis, which will allow the identification of innovative biomarkers of intracranial atherosclerosis stroke risk and potential treatment targets for future studies. By pursuing the following specific aims, the applicant will test his hypothesis and gather data for a clinical trial to reduce recurrent stroke risk in intracranial atherosclerosis (to be proposed in an R01 application during the K23 award period). Specific Aim 1 will test the hypothesis that ferumoxytol, the MRI contrast that labels macrophages, will be seen in arteries with intracranial atherosclerosis that recently caused stroke. Specific Aim 2 will test the hypothesis that arteries with intracranial atherosclerosis and ferumoxytol-labeled macrophages will have progression of the narrowing of the artery caused by intracranial atherosclerosis over a one-year period. Specific Aim 3 will test the hypothesis that arteries with intracranial atherosclerosis and ferumoxytol-labeled macrophages will have more strokes over a one-year period. The proposed research is significant because intracranial atherosclerosis is understudied and requires new approaches to reduce its risk. The proposed research is innovative because it combines an advanced imaging technique (vessel wall MRI) and a novel use of the macrophage-specific MRI contrast ferumoxytol, to provide multimodal insight into the mechanism of stroke from intracranial atherosclerosis that could be treated therapeutically using medications that target macrophages.